Nafarelin

Origin and structure

Nafarelin is a modified form of gonadotrophin-releasing hormone (GnRH, also called LHRH or gonadorelin), the ten-amino-acid hormone that the hypothalamus releases in pulses to make the pituitary produce LH and FSH. In 1982 John Nestor and colleagues described a series of GnRH analogues in which the glycine at position 6 was replaced by a bulky, water-repelling D-amino acid. The version with 3-(2-naphthyl)-D-alanine was about 200 times as potent as natural GnRH at suppressing the oestrous cycle of rats, among the strongest analogues reported at the time. That peptide is nafarelin: pGlu-His-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-Gly-NH2, formula C66H83N17O13, molar mass about 1322 g/mol. Like triptorelin, it differs from the natural hormone at that one position only.

The US company Syntex developed it as a nasal spray, the form in which it is sold: a solution of nafarelin acetate in a metered pump. Only a small part crosses the nasal lining: on average 2.8% of a dose reaches the blood (range 1.2 to 5.6%), levels peak 10 to 40 minutes after spraying, and the half-life is about three hours. Swallowed nafarelin is broken down in the gut and not absorbed, according to the labels. The peptide is degraded by peptidases rather than by the liver's cytochrome P450 enzymes, so the labels expect no pharmacokinetic drug interactions.

All the licensed products are Pfizer's: Synarel in the Netherlands, France, Spain, Ireland, the Czech Republic and the US, and Synarela in Germany and the Nordic countries, according to the EMA's 2021 product list and the US label.

How it works

Natural GnRH works because it reaches the pituitary in pulses. Nafarelin binds the same receptor but keeps it occupied, so the effect comes in two phases. First the pituitary releases more LH and FSH, and the ovaries or testes briefly make more sex hormones. With continued daily use that stimulation fades: the pituitary cells become desensitised, and after three to four weeks the output of sex hormones has fallen. In women oestrogen falls sharply into a temporary, menopause-like state, periods usually stop and ovulation is suppressed, and oestrogen-dependent tissue such as endometriosis and fibroids becomes inactive and can shrink. The effect is reversible: pituitary and ovarian function normally return within four to eight weeks of stopping.

Each use builds on one of these phases. In endometriosis, fibroids and early puberty the aim is the shutdown, and the first surge is a drawback: in the first two months some women have irregular bleeding, and ovarian cysts can form, often in women with polycystic ovaries. In IVF the spray keeps the pituitary quiet while the ovaries are stimulated with gonadotrophins, so that no premature LH surge spoils the cycle; an hCG injection then triggers the final maturation of the eggs. Because the spray only works while it is used, missed doses let the system restart, with breakthrough bleeding or even ovulation.

A blocked nose does not seem to matter much: in studies cited by the labels, rhinitis had no relevant effect on absorption. Decongestant sprays do: in the Dutch product information, oxymetazoline sprayed 30 minutes beforehand in people with recurring rhinitis cut the amount absorbed by 39% and the peak level by 49%, compared with people whose nasal lining was normal.

Is nafarelin approved?

Yes. Nafarelin is a prescription medicine in a number of EU countries and in the US, with indications that differ by country.

In the EU there is no central licence from the EMA: each product is authorised by a national regulator. The list from the EMA's 2021 safety assessment names Pfizer products in nine EU countries (the Czech Republic, Denmark, Finland, France, Germany, Ireland, the Netherlands, Spain and Sweden) and in Norway and Iceland. That review by the EMA's safety committee (PRAC) followed continued reports of ovarian hyperstimulation syndrome, some of them serious, and in October 2021 the CMDh, where the national regulators coordinate, agreed that the product information should warn of this risk when nafarelin is combined with gonadotrophins in IVF.

In the Netherlands Synarel nasal spray (Pfizer) has been registered since 14 October 1991 (RVG 15086) and is available only on prescription, from a specialist experienced in treating endometriosis and fibroids. The Dutch product information lists three uses: moderate to severe endometriosis; fibroids, only as treatment of at most three months before surgery, to relieve symptoms and shrink the uterus and fibroids; and suppressing the pituitary before ovarian stimulation for IVF. It is not licensed for early puberty in the Netherlands. Synarel is not included in the GVS, the system through which basic health insurance pays for pharmacy medicines. For endometriosis pain, the Farmacotherapeutisch Kompas puts painkillers and hormonal contraceptives or progestogens first, and GnRH agonists or antagonists, with add-back hormones, in specialist care.

In the US the FDA approved Synarel on 13 February 1990 for endometriosis, and on 26 February 1992 for central precocious puberty in children of both sexes, an orphan indication. Experience in endometriosis is limited to women aged 18 and over treated for six months, the label notes. IVF is not an approved US use; the label mentions reports of ovarian hyperstimulation syndrome when Synarel was used that way. The current label, revised in November 2025, warns of depression, convulsions, severe skin reactions reported with other GnRH agonists and, in children, raised pressure in the skull.

Our shop does not sell nafarelin. Nafarelin offered as a research chemical would not be Synarel: it would have no marketing authorisation, would not be made under a medicines licence, and may not be used in people.

What the research shows

Most of the evidence comes from the late 1980s and 1990s, when nafarelin was tested against danazol, then a standard endometriosis drug, and against other GnRH agonists in IVF. Only one of the trials below had a placebo group. The main results:

• Endometriosis against danazol (NEJM 1988): 213 women with endometriosis confirmed at laparoscopy were randomised to six months of nafarelin spray at one of two doses or danazol tablets, double-blind with placebo spray and tablets. At the second laparoscopy the disease had shrunk in more than 80% in each group; mean scores fell from 20.4 to 11.7 on the lower nafarelin dose, from 21.9 to 12.6 on the higher dose and from 18.4 to 10.5 on danazol, with no significant difference between groups. Danazol lowered HDL and raised LDL cholesterol and nafarelin did not, but nafarelin caused hot flushes and lower libido more often. Of the 149 women who then tried to conceive, 39% succeeded, at similar rates in all groups.
• Symptom relief (US label): in the trials behind the US label, 60% of women on the usual nafarelin dose were free of symptoms after six months, 32% had mild, 7% moderate and 1% severe symptoms. Six months after stopping, half of those who had been symptom-free still were. Periods had stopped in about 90% by day 120 and had returned in all women not pregnant within three months of stopping.
• Against a leuprorelin depot (J Reprod Med 1997): 192 women with endometriosis were randomised, double-blind, to nafarelin spray with monthly placebo injections or to monthly leuprorelin (leuprolide) depot injections with placebo spray, for six months. Both relieved symptoms and signs equally. Oestradiol stayed higher on nafarelin, and women on nafarelin lost less bone density and had fewer hot flushes.
• After surgery, against placebo (Fertil Steril 1997): 109 women whose endometriosis had been reduced by laparoscopic surgery received six months of nafarelin or placebo spray. Among those analysed, 31% on nafarelin (15 of 49) needed further treatment during follow-up, against 57% on placebo (25 of 44), and the median time until then was more than 24 months against 11.7 months. Pelvic pain scores reported by the women fell in both groups; the doctors' overall ratings improved only on nafarelin.
• IVF: a 2001 meta-analysis led by researchers at the drug company Pharmacia pooled nine randomised trials with 1,014 women, 597 of them on nafarelin and most of the others on buserelin. Pregnancy rates per embryo transfer were the same as with the other GnRH agonists, and women on nafarelin needed fewer ampoules of gonadotrophins and fewer days of stimulation.
• Early puberty (US label): in the trials behind the US label, breast development stopped or regressed in 82% of girls and genital development in all boys, but pubic hair, driven largely by the adrenal glands, did so in only 54%. In all 69 children followed for a year after stopping, puberty resumed. The safety data cover 155 children treated for an average of 41 months. The label describes these results without a comparison group.
• Trials under way (ClinicalTrials.gov, October 2026): in France, a phase 3 trial run by the Paris public hospital group AP-HP plans to enrol 652 women to test nafarelin spray as the only luteal support after a GnRH-agonist trigger and fresh embryo transfer, against an hCG trigger with vaginal progesterone, with live birth as the main outcome. In Spain, a trial by Fundación Dexeus that started in October 2026 compares nafarelin spray with a triptorelin injection as the trigger for final egg maturation in a planned 154 women freezing their eggs.

Side effects and warnings

Most side effects follow from the low oestrogen. In the US trials against danazol, about 90% of 203 women on nafarelin reported hot flushes, against about 70% on danazol, and roughly one in five reported lower libido, vaginal dryness or headache; mood swings, acne, muscle pain, smaller breasts and nasal irritation each affected around 10 to 15%. The Dutch product information, based on 282 treated adults, also lists weight gain, oedema, oily skin and rhinitis as very common, and depression, insomnia, tingling, higher or lower blood pressure, excess hair growth and allergic reactions as common. Danazol caused more weight gain, oedema and unfavourable cholesterol changes: at the end of treatment 43% of women on danazol had low HDL cholesterol, against none on nafarelin.

Bone loss is the main limit on treatment. After six months on nafarelin, the density of the spongy bone in the vertebrae had fallen by an average of 8.7% on CT and total vertebral bone mass by 4.3%; after treatment they recovered only partly, to 4.9% and 3.3% below the starting values. Measured by DEXA, spinal bone mass fell 3.2% and was 1.4% below baseline six months later, while the bones of the forearm and hand hardly changed. The labels set the course at six months and do not recommend repeat courses because safety data are lacking, especially in women with other risk factors for osteoporosis.

The labels also warn that depression can appear or worsen, and the US label lists post-marketing reports of suicidal thoughts and suicide attempts. Other warnings: convulsions; ovarian cysts in the first two months; ovarian hyperstimulation syndrome when nafarelin is combined with gonadotrophins in IVF; rare pituitary apoplexy (a sudden infarction of the pituitary), reported with GnRH agonists mainly in people found to have a pituitary adenoma, and mostly within two weeks of the first dose; and severe skin reactions reported with other GnRH agonists. The preservative benzalkonium chloride can make the nasal lining swell with long use. Nafarelin is contraindicated in pregnancy and breastfeeding.

In 155 children treated for early puberty in the US trials, most side effects came in the first six weeks, from the initial surge: acne in 10%, temporary breast enlargement and vaginal bleeding in 8% each, and mood swings in 6%; about 3% stopped because of side effects. The US label also warns of raised pressure in the skull (pseudotumour cerebri) in children on GnRH agonists, and scans during long treatment occasionally showed changes in the size or shape of the pituitary, of unknown significance.

Frequently asked questions

Is nafarelin (Synarel) available in the Netherlands?

Yes, on prescription. Synarel nasal spray from Pfizer has been registered in the Netherlands since 1991 for endometriosis, for fibroids in the three months before surgery, and for suppressing the pituitary in IVF. It is not licensed there for early puberty, and it is not included in the GVS, the system through which basic health insurance pays for pharmacy medicines. Nafarelin sold as a research chemical is not Synarel and may not be used in people.

Why can nafarelin cause bleeding at the start?

Because it first stimulates the pituitary before shutting it down. In the first two months the hormone swing can cause irregular bleeding, which the US label puts down to the fall in oestrogen and expects to stop by itself. If regular periods continue after two months, the label points to missed doses or too low a dose. In children with early puberty, vaginal bleeding or breast enlargement can occur in the first month and should fade soon after.

Is nafarelin a contraceptive?

No. At the usual dose it generally suppresses ovulation and stops periods, but the US label says it does not ensure contraception, particularly when doses are missed. Outside IVF, both labels call for a non-hormonal method during treatment, and the Dutch text says hormonal contraception must be stopped before treatment starts. Pregnancy must be ruled out before starting, because nafarelin is contraindicated in pregnancy: according to the US label it caused fetal deaths in rats and, in one of two rat studies, malformations.

Does nafarelin cause bone loss?

It thins bone while oestrogen is low, and the loss is only partly undone. After six months, the density of spongy bone in the vertebrae fell by an average of 8.7% on CT and was still 4.9% below baseline after treatment; DEXA scans showed a 3.2% loss, with 1.4% remaining six months after stopping. In the trial against a monthly leuprorelin depot, women on nafarelin lost less bone. The labels limit a course to six months and advise against repeat courses.

What is the difference between nafarelin and leuprorelin or triptorelin?

All three are GnRH agonists with the same two-phase action; they differ in form and licensed uses. Nafarelin is a nasal spray used every day, and its effect wears off within four to eight weeks of the last dose. Leuprorelin and triptorelin are injections, mostly slow-release depots, and are also licensed for prostate cancer. In a double-blind trial in endometriosis, nafarelin spray and a monthly leuprorelin depot relieved symptoms equally, with higher oestradiol, less bone loss and fewer hot flushes on nafarelin.

Is nafarelin banned in sport?

For men, yes, at all times, in and out of competition. The WADA Prohibited List 2026 names GnRH and its agonist analogues, with nafarelin by name, in class S2.2.1, testosterone-stimulating peptides in males. It is not prohibited for women. The Dutch translation of the list by the Dopingautoriteit carries the same text.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

Related peptides